AKT2, a member of the protein kinase B family, is activated by growth factors, v-Ha-ras, and v-src through phosphatidylinositol 3-kinase in human ovarian epithelial cancer cells

Three members have been identified in the protein kinase B (PKB) family, i.e., Akt/PKB alpha, AKT2/PKB beta, and AKT3/PKB gamma. Previous studies have demonstrated that only AKT2 is predominantly involved in human malignancies and has oncogenic activity. However, the mechanism of transforming activity of AKT2 is still not well understood. Here, we demonstrate the activation of AKT2 with several growth factors, including epidermal growth factor, insulin-like growth factor 1, insulin-like growth factor II, basic fibroblast growth factor, platelet-derived growth factor, and insulin, in human ovarian epithelial cancer cells. The kinase activity and the phosphorylation of AKT2 were induced by the growth factors and blocked by the phosphatidylinositol (PI) 3-kinase inhibitor, wortmannin, and dominant-negative Ras (N17Ras). Moreover, the activated Ras and v-Src, two proteins that transduce growth factor-generated signals, also activated AKT2, and this activation was not significantly enhanced by growth factor stimulation but was abrogated by wortmannin. These results indicate that AKT2 is a downstream target of PI 3-kinase and that Ras and Src function upstream of PI 3-kinase and mediate the activation of AKT2 by growth factors. The findings also provide further evidence that AKT2, in cooperation with Ras and Src, is important in the development of some human malignancies.     

The maximum watts factor as a measure of detrusor contractility independent of outlet resistance

The maximum watts factor (WFmax) is often used to characterize detrusor contractility. It was recently shown that the WFmax may increase in some patients with chronic outlet obstruction. It is, however, unclear whether this increase reflects a dependence of the WFmax on the degree of outlet obstruction or whether it represents a true increase in detrusor contractility secondary to chronic outlet obstruction. Therefore, this study was performed to investigate this issue using a canine model of acute outlet obstruction. Urodynamic studies were performed on adult canines with surgically exposed lower urinary tracts. Pressure transducers were used to measure the intravesical and the distal urethral pressures, whereas an ultrasonic flow meter was used to obtain a simultaneous measure of the urinary flow rate. Detrusor contractions were induced by electrically stimulating the pelvic nerves bilaterally. Varying degrees of outlet obstruction were created using an inflatable sphincter cuff secured around the bladder outlet. The WFmax, the detrusor pressure at voiding terminus (Pdet.clos), and the passive urethral resistance (R) were computed from measured pressure-flow rate data at each degree of outlet obstruction. The WFmax was not significantly correlated to either the sphincter cuff volume (r = 0.025, p = 0.871), the Pdet.clos (r = 0.286, p = 0.073) or the R (r = 0.110, p = 0.509). The WFmax was not significantly different among mild, moderate, and severe degrees of outlet obstruction (p = 0.176). Our results suggest that the WFmax is independent of the degree of acute outlet obstruction (defined in terms of the sphincter cuff volume, Pdet.clos and R). This validates the current practice of using the WFmax to evaluate detrusor function in patients with voiding dysfunction regardless of outlet resistance. Further, since the WFmax is independent of outlet obstruction acutely, it is reasonable that it would also be independent of outlet obstruction under chronic conditions. Our results, therefore, also imply that the increase in the WFmax with chronic outlet obstruction may represent a true increase in detrusor contractility and not a WFmax dependence on outlet resistance.     

Local recurrence of breast cancer after cytological evaluation of lumpectomy margins

Successful breast conservation therapy with optimal cosmesis requires adequate tumor excision and negative tumor margins. Therefore, more sensitive techniques are being developed to identify lumpectomy margins intraoperatively with greater accuracy. Unidentified microscopic disease is seemingly responsible for a local recurrence rate of up to 25 per cent 3 to 5 years after lumpectomy and radiotherapy for breast cancer patients. As a result, Moffitt Cancer Center has routinely used an intraoperative touch preparation cytology (TPC) protocol to evaluate the entire resected surface of all lumpectomies. In addition, resection margins were also evaluated by gross examination and by standard histology. In rare instances frozen sections were used to evaluate tumor margins. In this study 701 consecutive lumpectomy specimens were evaluated by TPC during the period of 9 years with a mean follow-up of 3.5 years. Local cancer recurrence was 2.7 per cent (mean recurrence, 2.53 years), in women whose lumpectomy margins were evaluated by TPC. Of interest, a local recurrence rate of 14.6 per cent was observed in patients who had referral lumpectomies evaluated by conventional histopathology. This study suggests that accurate margin assessment with TPC plays an important role in the control of local recurrence after breast conservation therapy. Therefore, we conclude the routine use of intraoperative TPC provides rapid, reliable, topographically accurate identification of residual microscopic disease at lumpectomy margins.     

HLA class-I and class-II antigen association in rheumatoid arthritis at Varanasi, India

We examined the localization of phosphotyrosine (p-Tyr)-modified proteins in the normal corneal epithelium using affinity-purified rabbit anti-p-Tyr antibody. Normal rat cornea was fixed and semi-thin and ultra-thin frozen sections were prepared. Immunofluorescence microscopy showed that p-Tyr was distributed along the cell membrane of the corneal epithelium. Immunogold electron microscopy revealed that the labeling is exclusively localized in the desmosomes and hemidesmosomes. A fraction enriched with desmosomes was extracted from the bovine corneal epithelium and examined by Western blotting. Immunoblotting for p-Tyr showed eight prominent bands (290, 200, 190, 115, 85, 62, 50, and 47 kD) in the desmosomal fraction. The enrichment of p-Tyr in desmosomes and hemidesmosomes of the corneal epithelium suggests that these cell-to-cell and cell-to-substrate junctions are involved in signal transduction.     

Associations between ADHD and psychoactive substance use disorders. Findings from a longitudinal study of high-risk siblings of ADHD children

This article investigates the relationship between attention-deficit/hyperactivity disorder (ADHD) and psychoactive substance use disorders (PSUD) in siblings of ADHD and normal-control probands and addresses issues of psychiatric comorbidity and gender. Using DSM-III-R structured diagnostic interviews and blind raters, the authors conducted a 4-year follow-up of siblings. ADHD and male gender predicted higher rates and an earlier onset of PSUD after adjusting for high-risk status, other psychiatric disorders, and age. Risk was particularly high if the siblings had ADHD plus conduct disorder. This study's findings confirms the authors' prior report high-lighting the importance of drug and alcohol prevention and cessation programs aimed at ADHD youth and their siblings, particularly those with comorbid conduct disorder.